1. Field of the Invention
The present invention relates generally to a system and methods for processing fine dispensable powders. More particularly, the present invention relates to a system and methods for forming fine powdered medicaments into agglomerates for easier processing, where the agglomerates are readily broken back down to the fine powder when needed for pulmonary delivery or other uses benefitting from fine powders.
Effective delivery to a patient is a critical aspect of any successful drug therapy. Various routes of delivery exist, and each has its own advantages and disadvantages. Oral drug delivery of tablets, capsules, elixirs, and the like, is perhaps the most convenient method, but many drugs are degraded in the digestive tract before they can be absorbed. Such degradation is a particular problem with modern protein drugs which are rapidly degraded by proteolytic enzymes in the digestive tract. Subcutaneous injection is frequently an effective route for systemic drug delivery, including the delivery of proteins, but enjoys a low patient acceptance. Since the need to inject drugs on a frequent schedule, such as insulin one or more times a day, can be a source of poor patient compliance, a variety of alternative routes of administration have been developed, including transdermal, intranasal, intrarectal, intravaginal, and pulmonary delivery.
Of particular interest to the present invention are pulmonary drug delivery procedures which rely on inhalation of a drug dispersion or aerosol by the patient so that the active drug within the dispersion can reach the distal (alveolar) regions of the lung. It has been found that certain drugs are readily absorbed through the alveolar region directly into blood circulation. Pulmonary delivery is particularly promising for the delivery of proteins and polypeptides which are difficult to deliver by other routes of administration. Such pulmonary delivery can be effective both for systemic delivery and for localized delivery to treat diseases of the lungs.
Pulmonary drug delivery (including both systemic and local) can itself be achieved by different approaches, including liquid nebulizers, metered dose inhalers (MDI's) and dry powder dispersion devices. Dry powder dispersion devices are particularly promising for delivering protein and polypeptide drugs which may be readily formulated as dry powders. Many otherwise labile proteins and polypeptides may be stably stored as lyophilized or spray-dried powders by themselves or in combination with suitable powder carriers.
The ability to deliver proteins and polypeptides as dry powders, however, is problematic in certain respects. The dosage of many protein and polypeptide drugs is often critical so it is necessary that any dry powder delivery system be able to accurately, and precisely (repeatably) deliver the intended amount of drug. Moreover, many proteins and polypeptides are quite expensive, typically being many times more costly than conventional drugs on a per-dose basis. Thus, the ability to efficiently deliver the dry powders to the target region of the lung with a minimal loss of drug is critical.
An exemplary dry powder dispersion device for efficiently delivering dry powder medicaments to the lungs is described in copending U.S. patent application Ser. No. 08/309,691, filed Sep. 21, 1994 (attorney docket no. 15225-5), the disclosure of which is herein incorporated by reference. Such a dispersion device is constructed to receive the powdered medicament in a receptacle having a puncturable lid or other access surface. The receptacle is placed in the device, and a feed tube is penetrated into the lid of the receptacle to provide access to the powdered medicament therein. A high velocity gas stream is then flowed past a portion of the tube, such as an outlet end, to draw powder from the receptacle, through the tube, and into the flowing gas stream to form an aerosol for inhalation by the patient.
Of particular interest to the present invention are the physical characteristics of the fine powders to be delivered by such apparatus, and particularly, the flowability of the fine powders. Most fine powders have poor flowability which can often be problematic when attempting to process, e.g. move and meter, the powders. For example, in the case of fine powder medicaments, poor flowability increases the time and/or reduces the accuracy of filling the receptacles with unit doses of the powdered medicaments for subsequent use in a powder inhaler. Therefore, a significant improvement in the powder flow will increase the probability for success of filling processes.
To improve the flowability of fine powder medicaments, some have proposed the use of a blending process where the powdered medicaments are combined or blended with larger carrier particles, such as coarse (i.e. greater than 25 .mu.m) lactose particles, which have easier handling and flowability characteristics. Use of a carrier, however, presents a variety of problems including dilution of the drug, requiring a larger dispersion volume for a given drug dosage, and the potential for poor content uniformity of the blend.
Another proposed process for improving flowability is to increase the size of small particles by agglomeration where the fine powders are combined into larger-sized aggregated units. Such aggregated units can be formed by a variety of processes including low shear granulation, high shear granulation, roller compaction or dry granulation, and extrusion. One particular concern with the formulation of inhalation powders into aggregated units is the resulting friability of the aggregated units, i.e. the ability of the aggregated units to be broken down to the fine powder. If the aggregated units are not sufficiently friable, they cannot be sufficiently broken down by an inhaler when used for pulmonary delivery. Another concern with the formulation of inhalation powders into aggregated units is their resulting size. The aggregated units should have a narrow size distribution so that they may be utilized in existing inhalation devices. For example, if the aggregated units are too large, they can become trapped within the holding receptacle and will not be delivered to the lungs.
The extrusion process is advantageous over other agglomeration processes in that it allows for the rapid formation of aggregated units in a specific size range using low pressures. In the extrusion process, the fine powder is wetted with a liquid, referred to as a binding liquid, and then forced through a screen to form an extrudate. The extrudate is then dried and sieved to break up the extrudate into the aggregated units. Typically, water, ethanol, glycerin, iso-propanol, or methanol are used as the binding liquid. One particular drawback to the use of such liquids is that a significant portion of proteins are susceptible to denaturation following exposure to alkanols. Alkanols and water can also solubilize excipients in the powder, such as carbohydrates and buffer salts. Excipients solubilized by the binding liquid can lead to the formation of strong crystalline bridges between particles, thereby strengthening the aggregated units and making them more difficult to disperse.
Hence, for these and other reasons, it would be desirable to provide improved systems and methods for agglomerating fine powders into aggregated units that would overcome or greatly reduce such problems. The systems and methods should allow for the aggregated units to be produced with a narrow size distribution and to have an appropriate level of friability, i.e. neither too high nor too low, so that the aggregated units can be used with existing dry power inhalers which require the break up of the aggregated units prior to inhalation. In one aspect, it would further be desirable to provide systems and methods for producing agglomerate powders with a binding liquid that does not interact with the hydrophilic or lipophilic components of the powder.
2. Description of the Background Art
Dry powder dispersion devices for medicaments are described in a variety of patent documents, including U.S. Pat. Nos. 4,137,914; 4,174,712; 4,524,769; 4,667,668; U.K. Patent Application No. 2,156,783; European Patent Application No. 87850060.2; and PCT Application Nos. PCT/SE93/00389; PCT/SE93/01053; and PCT/DK90/00005.
A process for providing water-soluble micronized substances is described in European Patent Application No. 92850062.8.
A system for administration of liposomes to mammals is described in European Patent Application No. 87850273.1.
U.S. Pat. No. 5,376,359 describes a method for making a stabilized aerosol drug formulation.
British Patent No. 1,151,017 describes a process for producing finely divided metal powders.
A variety of publications describe various powder inhalers including S. P. Newman et al., Deposition and clinical efficacy of turbutaline sulphate from Turbuhaler, a new multidose powder inhaler, Eur Respir J, 1989, 2:247-252; S. Pedersen, How to use a Rotahaler, Arch Dis Child, 1986, 61:11-14.
Dr. Gabrie M. H. Meesters, Not so dusty, describes market demand for free flowing powders through agglomeration.
Product brochures Fine-granulation technology, LCI Corporation, Processing Division, Charlotte, N.C. and Agglomeration: sizing up the agglomeration process, BEPEX Corporation, Minneapolis, Minn., .COPYRGT.1992, describe processes for producing agglomerated particles.
E. M. Phillips et al., Formulation Development of Spray Dried Powders for Inhalation (Abstract), Pharm. Res., 11(10), S-158, 1995 describes the aerosolization of spray dried powders.